Rosuvastatin and its pharmaceutically acceptable salts are one of HMG-CoA reductase inhibitors that inhibit the synthesis of cholesterol for the treatment of dyslipidemia. Crestor tablets (i.e., rosuvastatin calcium salts available by AstraZeneca), including rosuvastatin as a main ingredient, have been widely used both domestically and internationally for the treatment of dyslipidemia and dyslipidemia-related disorders. In particular, research has been reporting that rosuvastatin has excellent effects on lowering LDL cholesterol levels in blood and increasing beneficial HDL cholesterol levels in the body, as compared with effects of atorvastatin or simvastatin that is commercially available as a drug using the same mechanisms with rosuvastatin. Accordingly, there is an increasing interest in rosuvastatin formulation.
HMG-CoA reductase inhibitors are generally used in a combination with a therapeutic agent for treating dyslipidemia, the therapeutic agent using a different mechanism from that of the HMG-CoA reductase inhibitors, so that HMG-CoA reductase inhibitors may increase therapeutic effects. Among the combinations, due to good drug interaction between the HMG-CoA reductase inhibitor and ezetimibe, which is a drug inhibiting the re-absorption of cholesterol in the small intestine, a composite formulation consisting of these two ingredients are actively being studied. For example, Vytorin™, which is a composite formulation consisting of simvastatin and ezetimibe, has already demonstrated excellent pharmacological effects and stability thereof, and is currently available in the market with an excellent sales performance.
Rosuvastatin or a pharmaceutically acceptable salt thereof is generally known to be unstable in a strong acidic environment, and thus, is often designed as a pharmaceutical formulation that includes a basic stabilizer. However, in the case of ezetimibe, which is unstable in a strong basic environment, a large number of ezetimibe-related compounds are produced. Furthermore, in a specific basic pH environment, the related compounds are increased by the interaction between ezetimibe and rosuvastatin so significantly that a composite formulation of rosuvastatin and ezetimibe fails to be commercialized. Thus, due to rosuvastatin and ezetimibe having different stable pH conditions from each other, it is not easy to ensure the stability of the active ingredients, i.e., rosuvastatin and ezetimibe, when preparing the composite formulation of rosuvastatin and ezetimibe.
In addition, in order to prepare an effective composite formulation, it is necessary to ensure high bioavailability of the active ingredients. A dissolution pattern of active ingredients of a solid formulation for oral administration is closely related to the bioavailability of the formulation, wherein high dissolution rate is premised on high bioavailability. In general, the smaller the active ingredient particles are in size, the better the dissolution rates thereof are. Smaller particle sizes of the active ingredients increase the surface areas. However, the stability thereof is more likely to be affected by the surrounding environment (refer to WO2010/056039). Therefore, if active ingredients of a composite formulation have different stable pH conditions from each other as in the case of the composite formulation of rosuvastatin and ezetimibe, reduction in particle size may cause an increase in the production of the related compounds within the composite formulation. Thus, it is difficult to expect high dissolution rates by simply reducing the particle size of the active ingredients.